Epicenter of Health Care Transformation

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An Unsustainable Path
Better Prevention and Management of Chronic
Disease are Critical to Improving Health Outcomes
and Lowering Healthcare Costs
Source DeVol, R, Bedroussian, A, et al. An
Unhealthy America The Economic Burden of
Chronic Disease. The Milken Institute. October
2007.
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Our Leaders Agree

• In the future, when doctors can truly prescribe
  the right treatment, to the right person, at the
  right time, we will have a new level of precision
  and effectiveness that will provide the
  knowledge-driven power that is necessary to
  achieve our highest goals in healthcare reform
  including more effective disease prevention and
  early disease detection.
• HHS Secretary Kathleen Sebelius
• Senate confirmation hearings, April 2, 2009

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IGNITE is a unique non-profit medical research
institute in the national capital area aimed at
alleviating human suffering and transforming the
health care system using a new strategy Personal
ized Medicine
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Strategy

• Chronic disease RD focus align program with
  market needs from outset
• Deep molecular sub-classification of chronic
  disease (all heritable risk identified)
• Identify at-risk individuals from across the
  population via genetic risk factor testing
• Run distributed primary prevention trials
  facilitated by HIT network
• Apply results rapidly back to at-risk individuals
  via a robust translational infrastructure
  including a captured health care system
• Integrate health information technology to allow
  heritable risk information to be incorporated
  into point-of-care with clinical decision
  support
• Empower change across the personalized medicine
  ecosystem through policy, education, health
  economics, regulation
• Outcome Alleviate or delay the onset of chronic
  disease and decrease the time individuals are
  sick at the end of life and allow resources to
  care for more

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CASE STUDY Alzheimers
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Alzheimers Disease
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How AD Contributes to the Crisis
In Boomer Diseases, such as Alzheimers, Impact
and Costs Will Escalate Dramatically Without New
Interventions
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Baseline Estimate
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Delayed Onset Slowed Progression (6 yrs)
1500
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Estimated Number of People With AD (in millions)
1000
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500
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2
0
0
2000
2010
2020
2030
2040
2050
Adapted from The Lewin Group Report, June 2004,
Saving Lives. Saving Money Dividends for
Americans Investing in Alzheimer Research, The
Alzheimers Association (http//www.alz.org/Resour
ces/FactSheets/Lewin_FullReport1.pdf)
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Deep MOLECULAR SUB-CLASSIFICATION
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Molecular Scanning Technologies

• Chairman of NIH Microarray Consortium (15 NIH)
• 10 years of experience with Affymetrix platform
• 5 years experience with Illumina
• gt60,000 expression profiles run
• gt100,000 SNP arrays run (10k, 100k, 500k, 1M)
• Data warehousing
• First Genomics Collaborators , Center of
  Excellence, and TransMed site of Affymetrix
• NHLBI Programs in Genomic Applications
• NEI intramural contract site
• NIH Neuroscience Array Consortium
• NCI funded ALL catalog
• NIA funded Alzheimers disease catalog
• ADNI Consortium hub
• International Autism Genome Project Genotyping
  Site
• TCGA Biospecimen repository
• High throughput sequencing (Solexa, 454, ABI,
  Pacific Biosiences)

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The Shop
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NIH Neuroscience Microarray Consortium
Total Projects 455 (45,400 arrays)

• 1650 registered users
• 455 proposals submitted from about 114
  institutions around the country and from over 287
  different investigators

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Population-wide screening
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Population-based Genetic Risk Factor
ScreeningDavid Agus, MD Dietrich Stephan,
PhDSABIsaac Kohane, MD PhDDavid Botstein,
PhDSpencer Wells, PhD
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Extract the Total Heritable Risk for Chronic
Disease
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Customer Acquisition
PersonalizedWeb Portal
Ongoing Service
Laboratory
Bioinformatics
ATACCGCTGGCCCTTTGGCATTACCTATGAAGATTGCTTCAGCCAGCGTC
AGTTTCAACCTGTACGCTAGTGTGTTTCTACTCACGTGTCTCAGCATTGA
TCGATACCTGGCTATTGTTCACCCAATGAAGTCCC
FUTURE Full genome sequencing, copy number
analysis, methylation status leading to
personalized exposure mitigation strategies and
biomarker monitoring programs fully integrated
into the established health care system.
Navigenics CONFIDENTIAL
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Non-Invasive DNA Collection Kit
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GMP-compliant, ISO-certified Array Manufacturing
Photolithography
Chemistry
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QUALITYCLIA and stringent QC labCaptured
perfectly Per SNP algorithm checksPer SNP
concordanceH-W equilibrium checks
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What we do
Review world class academic and clinical research
published in leading peer-reviewed journals
and provide personalized, preventative, health
and wellness information
Navigenics CONFIDENTIAL
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Navigenics CONFIDENTIAL
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Stringent Curation Criteria

• Replication in the same ethnic group
• Once for GWAS, twice for candidate gene studies
• gt60 independent sample sets show same
  statistically significant effect with same allele
  (after trimming underpowered samples)
• Study design - An effort was made to sample
  controls from the same source population as the
  cases, e.g. ethnicity, gender, age, or other risk
  factors.
• Reasonable sample size to detect weak effects. OR
  lt1.5 needs 250 cases/250 controls at least.
• Significance level - Exact value depends on
  magnitude of the study (e.g. GWAS or candidate
  gene)
• Sound statistical design - correction for
  multiple testing, population stratification,
  confounding
• Sound laboratory practice - independent
  genotyping platforms, replicated samples
• Functional data and magnitude of effect are also
  taken into account, but studies are not
  automatically excluded if functional data is
  unavailable or the effect estimate is small.

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Finding the Relative Risk - see full details at
navigenics.com
Genotype Freq
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OR (RR)
? (RN)
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OR (RN)
? (RN)
Prevalence

• We normally get genotypic odds ratios RR/NN, RN/NN

• Using genotype frequencies and prevalence, we
  derive a set ofquadratic equations the
  solution provides the relative risks.

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Distribution of effect sizes for genetic and
environmental risk factors
Risk factors determined from literature using
strict curation guidelines
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Google, Microsoft, MDVIP, Cisco, etc
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Distribution of fold change in lifetime risk by
individual patient
Orange (gt1.2X)
Gray (lt1.2X)
Average lifetime risk for this condition
0.06 Individuals estimated lifetime risk
0.37 Fold change in ALTR 0.37/0.06 6.2
Fold ALTR
Individual Patient Number

• Across the entire population
• 98 of patients showed at least condition with
  gt1.2X increase in average lifetime risk
• 45 of patients showed at least condition with
  gt3X increase in average lifetime risk

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Conditions with gt3X ALTR risk by individual
patient
Fold ALTR
Individual Patient Number
Alzheimers disease Celiac disease Crohns
disease Glaucoma Graves disease Macular
degeneration Multiple sclerosis
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Alzheimers Disease Homozygous or Orange
30 APOE4 Heterozygous
3.3 APOE4 Homozygous
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Clinical Decision Support - Prevention
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GUIDE PATIENTS TO PRIMARY PREVENTION TRIALS
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fMRI in at-risk Individuals as a Surrogate for
Clinical Efficacy (BAI)

• push loaded patients to BAI via Navigenics
• baseline imaging performed
• patients go on drug and placebo
• periodic functional imaging
• use imaging as surrogate measure of clinical
  efficacy
• PROS
• hundreds of patients vs. thousands
• years vs. decades
• millions vs. hundreds of millions
• within patent life of compound
• CONS
• imagining not endpoint for approval
• no biomarker associated with imaging

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Deliver genome and CDS via HIT
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Health Information Technology Accelerates
Personalized Medicine

• Embed the genome into the electronic medical
  record (EMR)
• Role-based access to genome data (insurance
  companies excluded)
• Connect to a consumer-facing portal (PCHR,
  patientslikeme, Healthvault)
• Allow HIPAA-compliant messaging and
  interventional distributed trials
• Secure and authenticate transactions and data
  flow
• Undergird the clinical information system with a
  research database that can connect to other
  regional HIT systems (MS Amalga)
• Build a flexible clinical decision support module
  that allows physicians to understand
  molecularly-guided strategies
• Enable a learning CDS that constantly refines
  itself with the data flows to optimize clinical
  care

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Summary of Solution Alzheimers

• Identify genes that classify the population into
  high and low risk
• Build a broad-based CLIA genetic testing
  infrastructure to classify individuals across the
  world (Navigenics)
• Incorporate pointers to push high risk
  individuals into our clinical trial at BAI
• Develop functional brain imaging strategy that
  can detect the earliest brain changes associated
  with AD that can be used as a surrogate measure
  of clinical efficacy in slowing AD pathology
• Run a series of small trials drawing on a
  national base and fMRI to develop primary
  prevention drugs for AD in the next decade
• Work with the FDA so that fMRI and associated
  biomarkers are robust enough for approval of
  primary prevention therapies
• Use HIT vehicle to disseminate approved therapies
  back to population

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Results of Personalized Medicine in Chronic
Disease

• Genomic Profile / Predisposition / Environmental
  Risks

Family Members Health Care
Personal Health / Wellness (Disease pre-emption)
Interaction with Health Care Provider (Early
diagnosis if needed)
Learning Health Care System
Interventions (Targeted treatment individualized
to my molecular profile and that of my disease)
Post-Disease Management
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What Does Success Look Like?
Americans living longer without disease
American health care delivering value at reduced
cost
Connected information from bench to bedside
Robust pipeline of diagnostics and targeted
therapeutics moving toward approval
Growing portfolio of emerging, innovative
companies
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TRANSFORMING THE HEALTH CARE SYSTEM THROUGH
APPLIED RESEARCH IN THE NATIONAL CAPITAL
AREAInova Health SystemGeorge Mason
UniversityGeorge Washington University